Immunosuppression and Innate Immunity Control by Morbilliviruses Measles remains a leading cause of death among children because it suppresses immune function, facilitating secondary infections. The basic mechanisms underlying measles virus (MV)-induced immunosuppression are poorly understood, but in the first period of this grant we showed that the morbilliviruses MV and canine distemper virus (CDV) infect immune cells and replicate to high levels before causing acute disease. The extent of viral replication documented in immune cells implies that it can directly cause immunosuppression, which is a departure from previous assumptions about how morbilliviruses work. This new knowledge provides a different vantage point to study inactivation of immune function. From this vantage point we have developed a central hypothesis and several postulates that guide the next phase of experimentation. In particular, we raise the question of how morbillivirus infections progress undisturbed for several days in immune cells. Our central hypothesis is that these viruses have evolved a multi-pronged host cell control strategy that allow them to replicate to high levels in immune cells without the induction of danger signals (cytokines). We also postulate that this strategy is not fully effective in epithelial cells, resulting in strong innate and then adaptive immune responses. Since others and we have already identified three key regulators of immune activation that are targeted by MV proteins, we will use these three proteins as anchors for the analysis of the molecular and cellular mechanisms of virus spread. In aim 1, we will focus on how morbilliviruses control innate immunity at the molecular and cellular level, and we will test the postulate that this is based on concerted action of the viral V and P proteins on the transcription factors STAT1 and STAT2 and the cytoplasmic helicase protein mda5. In aim 2, we propose an "immune-cell-first" model of morbillivirus pathogenesis, with four postulates that we will confirm or deny. We will operate at the organism level also for aim 3: we will assess how specific interactions with key regulators of innate immunity slow down the adaptive immune response, favoring immunosuppression. PUBLIC HEALTH RELEVANCE: Immunosuppression after acute measles facilitates secondary infections, killing yearly almost half a million children. In the first period of this grant we showed that measles and related viruses infect immune cells and replicate to high levels before causing acute disease. Knowing this we developed a model of the early phases of pathogenesis with several postulates that we will test in natural hosts. We will infect these animals with recombinant viruses rendered incompetent to interact with key regulators of immune activation, or viral receptors, and we will document virulence and immunosuppressive activity. The results of this research will provide solid foundations for developing measles virus-based multivalent vaccines and cancer therapeutics.